In contrast to medicaments for humans, in the case of animal medicine the arising problems are completely different. A dosage in a form which is, for example, appropriate for oral consumption which has been tailored for human patients is not per se suitable for the administration to an animal. If, for example, a pharmaceutical active ingredient has a taste which is unpleasant to the animal, the animal will refuse to take it orally.
Furthermore, when the animals concerned are domestic animals, the animal keeper always prefers to use an easy and time-saving therapy to treat the animals. In addition simple and safe application forms are required, which, after diagnosis and indication by the veterinarian, can be given by the animal keeper himself/herself. Therefore, dosage forms are required which are eaten willingly and without problems by the animals, components which are found to be unpleasant or repulsive by the animal's sense of taste and smell should be avoided. In addition, an application form is required which allows the animal owner to control whether the administered dose has been taken up completely. This is e.g. achieved by offering a tablet which is voluntarily taken by the animal. Furthermore, in the particular situation the drug product is not administered by the patient (which is the diseased animal), but by the animal owner. Since any kind of interference will be stressful for the animal and as a result for the animal owner, the possibility of applying a free-choice medication will not only ensure convenience for the animal owner—especially for a drug product for the treatment of a chronic disease which has to be given over months once or twice a day—but will also support compliance by guaranteeing that the prescribed dose will be given and the treatment not terminated due to lack of acceptance.
Sometimes there are also stability problems with the active ingredient or ingredients contained in the medicaments which would result in an unavoidable loss of active ingredient(s), whereby the treatment effectivity and control of the therapy would be significantly violated.
Taking the above items into account, it is a basic aim of the present invention to develop a pharmaceutical combination form of the active substance pimobendan and an ACE inhibitor, both known in therapy to treat heart diseases in animals, and to provide an application form which is suitable for animal medicine, which can be used in a controlled manner without considerable effort and in a comfortable manner, such as on a daily basis, particularly for domestic animals, in the case of pets such as dogs and cats.
The characteristics and mode of action of the active substance pimobendan as well as the substance group of ACE inhibitors are known:
Pimobendan is the chemical substance (RS)-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one and has the following chemical formula:

It is a known cardiotonic vasodilator (inodilator) which derives its inotropic activity from a combination of phosphodiesterase III inhibition and sensitisation of myocardial contractile proteins to calcium. It is a chemically stable substance having a poor and pH-dependent solubility, it is better soluble in acid. The resorption, when administered orally, is prone to considerable inter- and intra-individual fluctuations if the active substance is incorporated in conventional pharmaceutical forms for oral administration. In solid medicaments pimobendan is often mixed with citric acid in order to improve the solubility and dissolution, and to maintain a potentially oversaturated solution as long as possible.
An ACE inhibitor is an angiotensin converting enzyme inhibitor which lowers blood pressure by inhibiting the formation of angiotensin II, thus relaxing the arteries, and consequently improves the pumping efficiency and cardiac output. ACE inhibitors are generally very difficult to formulate into dosage forms, as most ACE inhibitors on contact with some of the commonly used pharmaceutical ingredients undergo degradation at accelerated rates due to cyclization via internal nucleophilic attack to form substituted diketopiperazines or hydrolysis of the side chain ester group. For example, benazepril is a known ACE inhibitor. Benazepril is the chemical substance [S—(R*,R*J]-3-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid and has the following chemical formula:

It is a moisture and pH sensitive, well water-soluble and bitter tasting substance. In case of humidity a hydrolysis of benazepril or a pharmaceutically acceptable salt thereof is to be expected. Due to the very bitter taste it is difficult to formulate conventional palatable dosage forms.
The above substance-related particularities make it difficult to develop a pharmaceutical formulation wherein both active substances are present whereby a good long-term stability, the required release properties, and taste masking are provided.
In prior art a number of pharmaceutical formulations are described which contain an ACE inhibitor such as benazepril or a pharmaceutically acceptable salt thereof:
EP 1 490 037 B1 describes an animal medicine consisting of a substrate in pellet or tablet form, which is attractive to livestock and domestic animals and which consists of dry feed for animals on a vegetable and/or animal basis, in which fine-grained particles of a neutral-tasting, physiologically compatible, solid carrier material are embedded, whereby said fine-grained particles of carrier material have an average diameter of 0.09 to 0.8 mm and are coated with benazepril, and said benazepril layer is encased with a protective layer of a physiologically compatible polymer matrix. The physiologically compatible polymer matrix is selected from the group consisting of: shellac, a polymer on a cellulose, acrylic acid or methacrylic acid, maleic acid anhydride, polyvinyl pyrrolidone and polyvinyl alcohol basis. Also the production and usage of a preparation for veterinary medicine is disclosed.
EP 1 385 489 B1 is directed to granules based on angiotensin converting enzyme inhibitor, its isomers or its pharmaceutically acceptable salts, whereby they are coated and contain ACE inhibitor monocrystals, one or several binding agents selected from the group comprising in particular cellulosic polymers, in particular ethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose, acrylic polymers, polyvidones, polyvinyl alcohols, and mixtures thereof, optionally a diluent selected from the group consisting in particular of cellulosic derivatives, starches, lactose and polyols, in particular mannitol, and an anti-static agent selected from the group comprising in particular colloidal silica, precipitated silica and micronized or non-micronized talcum. Benazepril is mentioned as an example of an ACE inhibitor. It is also described the method for preparing said granules and rapidly disintegrating tablets based on the coated granules, which disaggregate in the mouth on contact with salvia in less than 60 seconds.
However, a pharmaceutical formulation containing an ACE inhibitor or a pharmaceutically acceptable salt thereof as well as pimobendan or a pharmaceutically acceptable salt thereof is not known up to now.
It is therefore an object of the present invention to provide an improved pharmaceutical formulation which avoids the disadvantages of the prior art and wherein an ACE inhibitor or a pharmaceutically acceptable salt thereof and pimobendan or a pharmaceutically acceptable salt thereof are present at the same time. The formulation shall allow to mask the bitter taste of the ACE inhibitor or a pharmaceutically acceptable salt thereof whereby the stability thereof shall be assured and the release of pimobendan or a pharmaceutically acceptable salt thereof shall not be hindered in any way. Preferably the combined formulation of both active substances shall be bioequivalent to the respective monoproducts. The choice of the excipients and/or additives contained in the formulation shall support and improve the stability of an ACE inhibitor or a pharmaceutically acceptable salt thereof present. Furthermore, the formulation shall not lead to particular inacceptance problems when administerd to animals, but should allow free uptake by the animal during chronic treatment over the whole administration period with equal or better acceptance compared to the existing individual tablet formulations containing either pimobendan or an ACE inhibitor as active pharmaceutical ingredient. In addition, a method of manufacturing the formulation shall be provided.